Diabetes is one of the most prevalent chronic worldwide disease with significant personal and financial costs to patients and their families, as well as for society. Diabetes can strike suddenly or lie undiagnosed for years while attacking the blood vessels and nerves. Diabetics, as a group, are far more often afflicted with blindness, heart disease, stroke, kidney disease, hearing loss, gangrene and impotence. One third of all visits to physicians are occasioned by this disease and its complications, and diabetes and its complications are a leading cause of untimely death in the United States and in the Western world.
Diabetes adversely affects the way the body uses sugars and starches which, during digestion, are converted into glucose. Insulin, a hormone produced by the pancreas, makes the glucose available to the body's cells for energy. In muscle, adipose (fat) and connective tissues, insulin facilitates the entry of glucose into the cells by an action on the cell membranes. The ingested glucose is normally converted in the liver to CO2 and H2O (50%); to glycogen (5%); and to fat (30-40%), the latter being stored in fat depots. Fatty acids from the adipose tissues are circulated, returned to the liver for re-synthesis of triacylglycerol and metabolized to ketone bodies for utilization by the tissues. The fatty acids are also metabolized by other organs. Fat formation is a major pathway for carbohydrate utilization.
Insulin deficiency is a common and serious pathologic condition in man. In insulin-dependent (IDDM or Type I) diabetes the pancreas produces little or no insulin, and insulin must be injected daily for the survival of the diabetic. In the second major type of diabetes, i.e., noninsulin-dependent (NIDDM or Type II) diabetes, the pancreas retains the ability to produce insulin and in fact may produce higher than normal amounts of insulin, but the amount of insulin is relatively insufficient, or less than fully effective, due to cellular resistance to insulin (Kosaka J., “The classification of disease based on the concept of Diabetes Mellitus”, Nippon Rinsho 1990 extra number, Diabetes Mellitus, Nippon Rinsho Press, Osaka 1990, p. 161-168).
The number of patients with NIDDM is large and it is said that, e.g., in Japan, more than 90% of patients who suffer from Diabetes show NIDDM. This corresponds to about two million individuals in Japan only who have NIDDM.
In most NIDDM subjects, the fundamental defects to which the abnormalities can be traced are (1) a reduced entry of glucose into various “peripheral” tissues and (2) an increased liberation of glucose into the circulation from the liver. There is therefore an extracellular glucose excess and an intracellular glucose deficiency. There is also a decrease in the entry of amino acids into muscle and an increase in lipolysis. Hyperlipoproteinemia is also a complication of diabetes. The cumulative effect of these diabetes-associated abnormalities is severe blood vessel and nerve damage.
The importance of delaying or preventing NIDDM and other conditions associated with insulin resistance cannot be over-emphasized. Untreated NIDDM can result in mortality due to cardiovascular disease and in other diabetic complications including retinopathy, nephropathy, and peripheral neuropathy. Insulin resistance can also cause hypertension, obesity, aging, and coronary artery diseases.
In recent years, the significance of insulin resistance in NIDDM has been realized and this has created a desire for the development of a medication which exhibits an antidiabetic action without stimulating insulin secretion by reducing insulin resistance in the target tissues of the insulin. Thiazolidine derivatives such as troglitazone and pioglitazone have been developed as compounds which possess such an action (Japanese Patent Applications Laid-open No. 22636/1980, No. 51189/1985, and No. 157522/1994). Some other thiazolidine derivatives with a bicyclic lactam structure or a cyclic urethane structure which exhibit similar actions have been reported (WO 92/07838, WO 92/07839, and WO 92/07850). Other therapeutic agents for NIDDM include (1) stimulants for synthesis of insulin and regulators for secretion of it as agents for disorder of the secretion and the production, (2) agents for absorption of sugar, stimulants for the utilization, agents for glucose transporter, or suppressors of gluconeogenesis in liver as agents for regulation of hyperglycemia, (3) stimulants for the action of insulin or antiglycation agents as a suppressor for disorder caused by hyperglycemia, and other anti-complication agents, have been developed.
However, the effect of these compounds with insulin resistance-reducing activity on decreasing blood glucose or lipids is not sufficient Development of a compound which exhibits a stronger anti-diabetic action has been desired.